Bone marrow neoplastic
Bone marrow - plasma cell and lymphoid neoplasms
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Cryoglobulinemia


Topic Completed: 26 February 2020

Minor changes: 16 March 2020

Copyright: 2001-2020, PathologyOutlines.com, Inc.

PubMed Search: Cryoglobulinemia[TI] bone marrow

Shuchi Zinzuwadia, B.S.
Ameet R. Kini, M.D., Ph.D.
Page views in 2019: 136
Page views in 2020 to date: 853
Cite this page: Zinzuwadia S, Mirza KM, Kini AR. Cryoglobulinemia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomacryoglobulins.html. Accessed August 11th, 2020.
Definition / general
  • See also topic in Kidney nontumor chapter
  • Cryoglobulinemia is a clinical disorder defined as the presence of immunoglobulins that precipitate below 37°C but redissolve upon warming
Essential features
  • Cryoglobulinemia is a clinical entity characterized by the presence of cryoglobulins in the serum
  • Cryoglobulins precipitate below normal body temperature (37°C) and dissolve on rewarming
  • Underlying causes of cryoglobulinemia include B cell / plasma cell malignances, infections such as hepatitis C virus and collagen vascular disorders such as Sjögren syndrome
  • Clinical features of cryoglobulinemia include the triad of purpura, arthralgia and weakness
ICD coding
  • ICD-10: D89.1 - cryoglobulinemia
Epidemiology
  • Overall prevalence is unknown (Lancet 2012;379:348)
  • Cryoglobulinemia is associated with infection (most frequently hepatitis C), autoimmune disease (e.g. Sjögren syndrome) and malignancy (B cell / plasma cell hematopoietic neoplasms)
  • 12 - 56% of hepatitis C virus patients have circulating cryoglobulins
  • Prevalence in patients coinfected with HIV and hepatitis C virus is 35 - 64%
Sites
  • Cold exposure leads to precipitation of cryoglobulins (typically in distal extremities) (Lancet 2012;379:348)
  • Internal organ involvement may occur
Pathophysiology
  • 3 types exist: type I (monoclonal IgM or monoclonal IgG), type II (mixture of monoclonal IgM and polyclonal IgG) and type III (polyclonal IgM and polyclonal IgG) (Blood 2017;129:289)
  • Type I cryoglobulinemia is characterized by hyperviscosity and occlusion of small blood vessels
  • In type II and III cryoglobulinemia, immune complexes are formed between monoclonal / polyclonal IgM and polyclonal IgG with RF formation and complement fixation
  • In hepatitis C virus (HCV) associated cryoglobulinemia, HCV drives a clonal B cell expansion producing monoclonal IgM that binds to anti-HCV IgG, forming immune complexes that promote vasculitis
Etiology
Clinical features
  • Purpura, arthralgia and weakness are noted in 80% of patients (Lancet 2012;379:348)
  • Type I cryoglobulinemia patients may present with hyperviscosity syndrome
  • Flares of immune complex mediated vasculitis can be seen
  • Joint pain may be present without inflammation
  • 20% of patients present with nephropathy
  • 17 - 60% present with peripheral neuropathy
  • Less common manifestations include gastrointestinal involvement, pulmonary involvement and myocardial vasculitis
Diagnosis
  • Cryoglobulins are identified by collecting blood (transported at 37°C) in a red top tube and dividing the serum into 3 tubes (Am J Hematol 2011;86:500)
    • First tube is used to quantify the amount of cryoprecipitate (cryocrit) by cooling to 4°C for up to 72 hours
    • Second tube is used to identify and analyze the cryoprecipitate
    • Third tube is used to demonstrate solubility of the cryoprecipitate on rewarming to 37°C
  • Diagnosis of underlying conditions is made on clinical, laboratory and histopathologic findings
Laboratory
  • Monoclonal gammopathy in types I and II (Lancet 2012;379:348)
  • Hyperviscosity
  • Unexplained low complement (C4)
  • Unexplained high rheumatoid factor
  • Raised serum creatinine
  • Microscopic hematuria and red blood cell casts
Prognostic factors
  • Worse outcome with older age, renal insufficiency, pulmonary involvement and gastrointestinal involvement
Case reports
  • 47 year old man with persistent mixed cryoglobulinemia despite successful treatment of hepatitis C, aggressive B cell directed therapies and long term plasma exchanges (Kidney Int Rep 2019;4:1194)
  • 55 year old woman with IgG4 related sialadenitis complicated with type III mixed cryoglobulinemia (Medicine (Baltimore) 2019;98:e16571)
  • 56 year old man with type I immunoglobulin M cryoglobulinemic vasculitis with chronic lymphocytic leukemia and a history of hepatitis C virus (Cureus 2019;11:e4729)
  • 58 year old woman with severe cutaneous necrosis associated with type I cryoglobulinemia (JAAD Case Rep 2019;5:736)
Treatment
  • Treatment is based on underlying pathogenesis (Lancet 2012;379:348)
  • Conventional immunosuppression: similar to treatment of other vasculitides
  • Apheresis: removes cryoglobulin from circulation
  • Antiviral therapy: for hepatitis C virus related cryoglobulinemia
  • Biologics: rituximab driven B cell depletion
Microscopic (histologic) description
  • Precipitated cryoglobulin appear as hyaline thrombi that occlude blood vessels (Lancet 2012;379:348)
  • In the kidney, glomeruli may show a membranoproliferative pattern of injury with PAS positive intracapillary deposits and double contour basement membrane
  • Vasculitis may involve small and medium sized blood vessels; skin, kidney and nerves are most commonly affected
Microscopic (histologic) images

Contributed by Maria M. Picken, M.D., Ph.D.

Cryoglobulinemic nephropathy

Peripheral smear description
  • Cryoglobulins (seen as pale staining material), rouleaux formation, pseudothrombocytosis
Peripheral smear images

Contributed by Anas Nasir, M.Sc.

Circulating cryoglobulins

Videos

Managing HCV cryoglobulinemia

Cryoglobulinemia and vasculitis

Differential diagnosis and management of cryoglobulinemia


Cryoglobulinemia, lymphoproliferation and hepatitis C

Pathology of cryoglobulinemic glomerulonephritis

Differential diagnosis
Board review style question #1
A 62 year old woman has increasing weight loss, fatigue and lack of appetite over the past 7 months. She is now complaining of intermittent headaches, dizziness and decreased vision bilaterally. Her hands get cold easily and she gets frequent nosebleeds. On physical exam, she has generalized lymphadenopathy. Laboratory studies show presence of cryoglobulin. Serum electrophoresis / immunofixation is pictured below (ELP = serum electrophoresis, G = IgG, A = IgA, M = IgM, K = kappa, L = lambda). Which underlying condition is most likely in this patient?



  1. Henoch-Schönlein purpura
  2. Hepatitis C infection
  3. Sjögren syndrome
  4. Systemic lupus erythematosus
  5. Waldenström macroglobulinemia
Board review answer #1
E. Waldenström macroglobulinemia

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Reference: Cryoglobulinemia
Board review style question #2
A 58 year old man with a medical history significant for hypertension, hyperlipidemia and diabetes presents to the clinic for a 5 month history of oliguria, arthralgia and fatigue. Physical exam shows needle track marks in his left antecubital fossa. Urinalysis shows microscopic hematuria. Serum creatine is increased and complement levels are decreased. Which of the following antibodies is most likely to be detected on further laboratory evaluation?

  1. Anti centromere antibody
  2. Anti desmosome antibody
  3. Anti glomerular basement antibody
  4. Anti hemidesmosome antibody
  5. Anti hepatitis C antibody
Board review answer #2
E. Anti hepatitis C antibody

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Reference: Cryoglobulinemia
Board review style question #3
A 54 year old African American man with hepatitis C and hypertension presents to his physician for recurrent joint pains, decreased urination and fatigue, which has been ongoing for the past 3 months. Physical examination shows several nonblanching purpuric papules on the patient's lower extremities and trunk. Urinalysis is positive for red blood cell casts. Renal biopsy is most likely to show which of the following?

  1. Crescent moon shape on light microscopy
  2. Mesangial expansion with eosinophilic nodular glomerulosclerosis on light microscopy
  3. Normal renal biopsy
  4. PAS positive intracapillary deposits with double contour basement membrane
  5. Podocyte hypertrophy, capillary wall thickening and diffuse glomerular sclerosis
Board review answer #3
D. PAS positive intracapillary deposits with double contour basement membrane

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Reference: Cryoglobulinemia
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